This application is a 371 of PCT/GB00/02756 filed Jul. 8, 2000.
The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) is families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1xcex1 and 1xcex2 (MIP-1xcex1 and MIP-1xcex2).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
In accordance with the present invention, there is provided a compound of formula (I) 
wherein:
R1 and R2 independently represent phenyl optionally substituted by halogen, C1 to 6 alkyl, nitro, cyano, hydroxy, methylenedioxy, C1 to 6 alkoxy, C1 to 6 haloalkyl, C1 to 6 haloalkoxy or C1 to 6 alkylsulphonyl;
each R3 independently represents halogen, nitro, C1 to 6 alkyl, cyano, C1 to 6 haloalkyl, hydroxy or C1 to 6 alkoxy; each alkoxy group being optionally further substituted by halogen, NR5R6, CO2R7, CONR8R9, pyrazolidinone, or a five membered heteroaromatic ring incorporating one to three heteroatoms independently selected from N, O and S; said heteroaromatic ring being optionally further substsituted by one or more C1 to 4 alkyl groups;
n represents an integer 0 to 3;
R4 represents hydrogen, hydroxy or NR10R11;
A represents xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94 or a bond;
Q represents C1 to 4 alkylene;
U, W and X independently represent carbon, optionally substituted by C1 to 4 alkyl, or nitrogen;
V represents nitrogen, optionally substituted by C1 to 4 alkyl, or oxygen;
Y represents C1 to 4 alkylene or xe2x80x94COxe2x80x94;
R5, R6, R7, R8, R9 independently represent hydrogen or C1 to 6 alkyl;
R10 and R11 independently represent hydrogen, C2 to 6 unsaturated alkyl or C1 to 6 alkyl; each alkyl group being optionally further substituted by CO2R12, hydroxy, C1 to 6 alkoxy, CONH2, NR13R14, OCH2CH2OH, or a five or six membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms selected from N, O and S; said ring optionally comprising one ring carbon atom that forms a carbonyl group; and said ring being optionally further substituted by C1 to 4 alkyl;
or the group NR10R11 together represents a 4 to 8 membered saturated azacyclic ring system; said ring optionally comprising one additional ring heteroatom selected from N, O and S; said ring optionally comprising one ring carbon atom that forms a carbonyl group; and said ring being optionally further substituted by C1 to 6 alkyl, C1 to 6 hydroxyalkyl, hydroxy, CO2R15, CONH2, CHO or COCH3;
R12 and R15 independently represent hydrogen or C1 to 4 alkyl; and
R13 and R14 independently represent hydrogen, C1 to 4 alkyl or C1 to 4 alkanoyl;
or a pharmaceutically acceptable salt or solvate thereof.
In one preferred embodiment, V represents nitrogen.
Preferably, R3 represents halogen. More preferably, R3 represents chlorine.
The term xe2x80x9cC1 to 6 alkylxe2x80x9d referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms and/or a cyclic alkyl group having from 3 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopentyl, methylcyclopentyl and cyclohexyl.
The term xe2x80x9cC1 to 4 alkylxe2x80x9d is to be interpreted analogously.
The term xe2x80x9cC2 to 6 unsaturated alkylxe2x80x9d referred to herein denotes a straight or branched chain alkyl group having from 2 to 6 carbon atoms and including one double bond or one triple is bond or a cyclic alkyl group having from 3 to 6 carbon atoms and including one double bond. Examples of such groups include ethenyl, ethynyl, 1- and 2-propenyl, 1- and 2-propynyl, 2-methyl-2-propenyl, 2-butenyl, 2-butynyl, cyclopentenyl and cyclohexenyl.
The term xe2x80x9cC1 to 6 alkoxyxe2x80x9d referred to herein denotes an oxygen atom bonded to a straight or branched chain alkyl group having from 1 to 6 carbon atoms or an oxygen atom bonded to a cyclic alkyl group having from 3 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, cyclopropyloxy and cyclohexyloxy.
The term xe2x80x9chalogenxe2x80x9d referred to herein denotes fluorine, chlorine, bromine and iodine.
The terms xe2x80x9cC1 to 6 haloalkylxe2x80x9d (for example, chloromethyl, 2-fluoroethyl and trifluoromethyl), xe2x80x9cC1 to 6 haloalkoxyxe2x80x9d (for example, trifluoromethoxy) and xe2x80x9cC1 to 6 hydroxyalkylxe2x80x9d (for example, hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl) are to be interpreted analogously.
Similarly, the term xe2x80x9cC1 to 6 alkylsulphonylxe2x80x9d represents such groups as methylsulphonyl, t-butylsulphonyl and cyclohexylsulphonyl.
The term xe2x80x9cC1 to 4 alkanoylxe2x80x9d referred to herein denotes a carbonyl group bonded to a straight or branched chain alkyl group having from 1 to 3 carbon atoms. Examples of such groups include acetyl and propionyl.
Examples of a xe2x80x9cfive membered heteroaromatic ring incorporating one to three heteroatoms independently selected from N, O and Sxe2x80x9d include furan, thiophene, imidazole, isoxazole, thiazole and triazole.
Examples of a xe2x80x9cfive or six membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms selected from N, O and S; said ring optionally comprising one ring carbon atom that forms a carbonyl groupxe2x80x9d include morpholine, pyrrolidine, pyridine, tetrahydrofuran, imidazole, pyrrolidone, piperidone and piperazine.
Examples of a xe2x80x9c4 to 8 membered saturated azacyclic ring system optionally incorporating one further heteroatom independently selected from N, O and Sxe2x80x9d include pyrrolidine, piperidine, morpholine, piperazine, pyrazolidine, imidazolidine, and perhydroazepine.
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
Examples of particular compounds of the invention include:
1-[(1-benzyl-1H-pyrazol-3-yl)methyl]-4,4-diphenylpiperidine;
1-{[1-(3-chlorobenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(3,4-dimethylbenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(4-methylbenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
4,4-diphenyl-1-({1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-3-yl}methyl)piperidine;
1-{[1-(2,4-dichlorobenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(3,4-dichlorobenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(3,4-difluorobenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(4-chlorobenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(4-fluorobenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(4-chloro-2-methoxybenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenol;
2-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenoxy]-N,N-dimethylacetamide;
1-{[1-(4-chlorobenzyl)-1H-imidazol-4-yl]methyl}-4,4-diphenylpiperidine;
1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazole-4-carbaldehyde;
{1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methanol;
1-{[1-(4-chlorobenzyl)-1H-1,2,3-triazol-5-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-4,4-diphenylpiperidine;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazole-5-carboxylic acid;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazole-5-carboxamide;
1-{[2-(4-chlorobenzyl)-1H-imidazol-5-yl]methyl}-4,4-diphenylpiperidine;
1-{[2-(4-chlorobenzyl)-1-methyl-1H-imidazol-5-yl]methyl}-4,4-diphenylpiperidine;
1-{[2-(4-chlorobenzyl)-3-methyl-3H-imidazol-5-yl]methyl}-4,4-diphenylpiperidine;
[2-(4-chlorobenzyl)-1H-imidazol-5-yl](4,4-diphenyl-1-piperidinyl)methanone;
2-[4-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-1-piperazinyl]-1-ethanol;
4-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-1-piperazinecarbaldehyde;
1-[4-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-1-piperazinyl]-1-ethanone;
N1-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-N1,N2,N2-trimethyl-1,2-ethanediamine;
N-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-2-(4-morpholinyl)-1-ethanamine;
1-{[4-(1-azetidinylmethyl)-1-(4-chlorobenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
N-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-2-(1-pyrrolidinyl)-1-ethanamine;
N-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-beta-alanine;
2-[({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl)methyl}amino]acetic acid;
N-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-2-(2-pyridinyl)-1-ethanamine;
{1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}-N-(4-pyridinylmethyl)methanamine;
2-[1-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-4-piperidinyl]-1-ethanol;
1-({1-(4-chlorobenzyl)-3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-4-yl}methyl)-4-methyl-1,4-diazepane;
3-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}metayl)phenoxy]-N,N-dimethyl-1-propanamine;
2-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenoxy]acetic acid;
2-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenoxy]acetamide;
2-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenoxy]-N,N-dimethylacetamide;
2-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenoxy]-N,N-diethylacetamide;
2-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenoxy]propanamide;
2-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenoxy]-N-methylacetamide;
1-{2-[5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenoxy]acetyl}-3-pyrazolidinone;
1-[(1-{4-chloro-2-[(3,5-dimethyl-4-isoxazolyl)methoxy]benzyl}-1H-pyrazol-3-yl)methyl]-4,4-diphenylpiperidine;
5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenyl (1-methyl-1H-imidazol-2-yl)methyl ether;
5-chloro-2-({3-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-pyrazol-1-yl}methyl)phenyl (2-methyl-1,3-thiazol-4-yl)methyl ether;
{1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}(4-morpholinyl)methanone;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N,N-dimethyl-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(2-methoxyethyl)-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(4-hydroxycyclohexyl)-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[1-(hydroxymethyl)propyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(tetrahydro-2-furanylmethyl)-1H-imidazole-5-carboxamide;
{1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}[2-(hydroxymethyl)-1-piperidinyl]methanone;
1-(4-chlorobenzyl)-N-[3-(diethylamino)propyl]-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazole-5-carboxamide;
{1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}[3-(hydroxymethyl)-1-piperidinyl]methanone;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(2-hydroxyethyl)-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(2-hydroxyethyl)-N-methyl-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[3-(1H-imidazol-1-yl)propyl]-1H-imidazole-5-carboxamide;
{1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}(1-pyrrolidinyl)methanone;
{1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}(3-hydroxy-1-pyrrolidinyl)methanone;
1-[4-({1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}carbonyl)-1-piperazinyl]-1-ethanone;
{1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}(1-piperidinyl)methanone;
1-(4-chlorobenzyl)-N-[2-(diethylamino)ethyl-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(2-hydroxyethyl)-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[2-(4-morpholinyl)ethyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-ethyl-N-(2-hydroxyethyl)-1H-imidazole-5-carboxamide;
{1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}(4-ethyl-1-piperazinyl)methanone;
N-(2-amino-2-oxoethyl)-1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[2-(1-pyrrolidinyl)ethyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[2-(1H-imidazol-4-yl)ethyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-methyl-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-N-(2,3-dihydroxypropyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[(1-ethyl-2-pyrrolidinyl)methyl]-1H-imidazole-5-carboxamide;
ethyl 1-({1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}carbonyl)-4-piperidinecarboxylate;
ethyl 1-({1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl]carbonyl)-3-piperidinecarboxylate; methyl 3-[({1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}carbonyl)amino]propanoate;
methyl 2-[({1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}carbonyl)amino]acetate;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(2-pyridinylmethyl)-1H-2-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[2-(2-pyridinyl)ethyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(3-pyridinylmethyl)-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(2-hydroxy-1,1-dimethylethyl)-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(2-hydroxy-1-methylethyl)-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1H-imidazole-5-carboxamide;
N-[2-(acetylamino)ethyl]-1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[2-(2-hydroxyethoxy)ethyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[1-(hydroxymethyl)cyclopentyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-1H-imidazole-5-carboxamide;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(3-methoxypropyl)-1H-imidazole-5-carboxamide;
1-({1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}carbonyl)-2-pyrrolidinecarboxamide;
1-({1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}carbonyl)-2-pyrrolidinecarboxamide;
{1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}[4-(2-hydroxyethyl)-1-piperidinyl]methanone;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-(2-propynyl)-1H-imidazole-5-carboxamide;
4-({1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-1H-imidazol-5-yl}carbonyl)-2-piperazinone;
1-(4-chlorobenzyl)-4-[(4,4-diphenyl-1-piperidinyl)methyl]-N-[1-(hydroxymethyl)propyl]-1H-imidazole-5-carboxamide;
1-{3-(4-chlorobenzyl)-[1,2,4]oxadiazol-5-ylmethyl}4,4-diphenylpiperidine;
and pharmaceutically acceptable salts and solvates thereof.
The present invention further provides a process for the preparation of a compound of formula (I) which comprises:
(i) when Y represents CH2,
reductive amination of a compound of general formula (II) 
wherein R3, R4, A, Q, U, V, W, X and n are as defined in formula (I),
with a compound of formula (III) 
wherein R1 and R2 are as defined in formula (I); or
(ii) when Y represents C1 to 4 alkyl,
reacting a compound of general formula (IV) 
wherein R3, R4, A, Q, U, V, W, X and n are as defined in formula (I) and L1 is a leaving group,
with a compound of formula (III); or
(iii) when Y represents CO, reacting a compound of general formula (V) 
wherein R3, R4, A, Q. U, V, W, X and n are as defined in formula (I) and L is a leaving group,
with a compound of formula (III); or
(iv) when at least one R group in formula (I) represents optionally substituted
reacting a compound of formula (VI) 
wherein R1, R2, R3, R4, A, Q, U, V, W, X, Y and n are as defined in formula (I), with a compound of formula (VII)
Rxe2x80x94L3xe2x80x83xe2x80x83(VII)
wherein R3 is such that the resultant group OR represents an optionally substituted C1 to 6 alkoxy group as defined for R3 in formula (I), and L is a leaving group;
(v) when A represents CO and R4 represents NR10OR11,
reacting a compound of formula (VIII) 
wherein R1, R2, R3, Q, U, V, W, X, Y and n are as defined in formula (I), and L4 is a leaving group, with a compound of formula (IX)
HNR10R11xe2x80x83xe2x80x83(IX)
wherein R10 and R11 are as defined in formula (I); or
(vi) when A represents CH2 and R4 represents NR10R11,
reductive amination of a compound of formula (X) 
wherein R1, R2, R3, Q, U, V, W, X, Y and n are as defined in formula (I), with a compound of formula (IX)
xe2x80x83HNR10R11xe2x80x83xe2x80x83(IX)
wherein R10 and R11 are as defined in formula (I); or
(vii) when Q is bonded to V and V represents nitrogen,
reacting a compound of formula (XI) 
wherein R1, R2, R4, A, U, W, X and Y are as defined in formula (I), with a compound of formula (XII) 
wherein R3, Q and n are as defined in formula (I) and L5 is a leaving group;
and optionally after (i), (ii), (iii), (iv), (v), (vi) or (vii) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
Salts of compounds of formula (I) may be formed by reacting the free base or another salt thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent in which the salt is insoluble, or in a solvent in which the salt is soluble, followed by subsequent removal of the solvent in vacuo or by freeze drying. Suitable solvents include, for example, water, dioxan, ethanol, 2-propanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The reaction may also be carried out on an ion exchange resin.
In processes (i) and (vi), the reductive amination reaction generally takes place under conditions which will be known to persons skilled in the art. For example, treatment of an aldehyde with an amine in the presence of a reducing agent in an inert solvent. Suitable reducing systems include catalytic hydrogenation or borane and derivatives thereof. A partial list of such reagents can be found in xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, J. March (1985) 3rd Edition on page 799.
In processes (ii) and (vii), the reaction is performed by treating an amine of general formula (III) or (XI) with an electrophile of general formula (IV) or (XII) respectively in an inert solvent. Suitable leaving groups L and L include sulfonate, trifluorosulfonate, mesylate, tosylate, and halides selected from the group chloride, bromide or iodide. The reaction is generally performed in the presence of a base. This base can be either an excess of the amine nucleophile or can be an additive to the reaction mixture. Potential basic additives are metal carbonates, especially alkali metal carbonates such as cesium carbonate, metal oxides and hydroxides, and tertiary amine bases. Suitable organic solvents are those such as acetonitrile, dioxane, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, tetrahydrofuran, dimethylsulfoxide, sulfolane and C1 to 4 alcohols. In a preferred embodiment, the leaving group is chloride.
In processes (iii) and (v) above, the reaction will take place on stirring a mixture of the reactants in a suitable organic solvent at a suitable temperature, generally between 0xc2x0 C. and the boiling point of the solvent. The reaction time will depend inter alia on the solvent used, the reaction temperature and the nature of the leaving group. The reaction may be catalysed by the addition of a base; bases that may be used include organic amines (for example, triethylamine or pyridine) and alkali metal hydroxides, alkoxides, carbonates or hydrides.
Suitable leaving groups, L2 and L4, include halogen (especially chlorine) and hydroxyl. When the leaving group is OH, the reaction between compounds of formulae (V) and (In), or between compounds of formulae (VIII) and (IX) may also be achieved using a suitable coupling agent such as CDI (1,1xe2x80x2-carbonyldiimidazole), DCC (1,3-dicyclohexylcarbodiimide) or HOBt (1-hydroxybenzotriazole).
In process (iv), the reaction will generally take place under similar conditions to those described above for processes (ii) and (vii).
In general, compounds of formulae (H), (IV), (V), (VI), (VII) (X) and (XI) may be prepared using similar types of reactions to those described above for compounds of formula (I).
Compounds of formula (H) wherein Q is bonded to V and V represents nitrogen, may be prepared by reaction of a compound of formula (XIII) 
wherein A, U, W, X and R4 are as defined in formula (I), with a compound of formula (XII) using conditions similar to those described above for processes (ii) and (vii).
Compounds of formulae (IV), (V) or (VIII) wherein L1, L2 and L4 respectively are leaving groups may be prepared from the corresponding compounds wherein L1, L2 and L4 are OH using reactions that will be readily apparent to the man skilled in the art. Thus, for example, using thionyl chloride or methanesulphonyl chloride in the presence of a suitable base such as triethylamine.
Compounds of formulae (IV) or (V) wherein L1 and L2 are OH and wherein Q is bonded to V and V represents nitrogen, may be prepared by a process analogous to that described above for compounds of formula (II).
Compounds of formula (VI) may be prepared by demethylation of a corresponding compound of formula (XIV) 
wherein R1, R2, R3, R4, A, Q, U, V, W, X, Y and n areas defined in formula (I), using, for example, boron tribromide.
Compounds of formula (X) may be prepared by formylation of a corresponding compound of formula (XV) 
wherein R1, R2, R3, Q, U, V, W, X, Y and n are as defined in formula (I), using for example phosphorus oxychloride in N,N-dimethylformamide.
Compounds of formula (II) may be similarly prepared by formylation of a corresponding compound of formula (XVI) 
Certain novel intermediates of formulae (II), (IV), (V), (VI), (VII), (X), (XI), (XV) and (XVI) form another aspect of the invention.
Compounds of formulae (III), (VII), (IX), (XII) and (XII) are either commercially available, or are known in the literature or may be prepared using known techniques.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups.
The protection and deprotection of functional groups is described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.
The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor activity. More particularly, the compounds have utility as modulators of the activity of chemokine receptors CCR1 and/or CCR3.
A further aspect of the invention involves the use of a compound of general formula (I) in the treatment of conditions or diseases in which modulation of chemokine receptor activity is beneficial.
Thus, compounds of general formula (I) may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
Examples of these conditions include:
(1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer""s lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
(2) (bone and joints) rheumatoid arthritis, osteoarthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter""s disease), Behcet""s disease, Sjogren""s syndrome and systemic sclerosis;
(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn""s disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; and
(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
Thus, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term xe2x80x9ctherapyxe2x80x9d also includes xe2x80x9cprophylaxisxe2x80x9d unless there are specific indications to the contrary. The terms xe2x80x9ctherapeuticxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
The invention also provides a method of treating an inflammatory disease in a person suffering from, or at risk of, said disease, which comprises administering to the person a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.